PROJECT SUMMARY/ABSTRACT Rheumatoid arthritis (RA) and Juvenile Idiopathic Arthritis (JIA) are leading causes of pain and disability. While treatment with biologic agents may improve outcomes, treatment failure is common in patients who are obese. Despite the significant impact of treatment failure, it is currently unknown if the poor drug response in obesity is due to physiologic changes altering drug pharmacokinetics (PK)/Pharmacodynamics (PD), the underlying inflammatory state, or both. Dr. Balevic proposes to respond to this need by 1) characterizing the effects of obesity on disease activity and biomarkers of inflammation in a prospective observational study in RA and JIA; 2) using PK/PD modeling to investigate the effect of obesity on drug levels for a probe biologic agent, and relate drug levels to disease activity; and 3) using the PK/PD model to evaluate an optimal dosing strategy in a PK/PD clinical trial. This Mentored Career Development Award will provide a structured learning environment and expert mentorship to enable Dr. Stephen Balevic to develop as an independent investigator and future leader in the field of therapeutics for adults and children with rheumatic disease. Dr. Balevic?s overarching career goal is to optimize the dosing, safety, and effectiveness of medications by integrating clinical pharmacology and PK/PD modeling with drug trials. To achieve this goal, Dr. Balevic created a career development plan that capitalizes on the longstanding collaboration between Duke University, where he is junior faculty in the Divisions of Adult and Pediatric Rheumatology/Duke Clinical Research Institute, and the University of North Carolina at Chapel Hill, where he is pursuing a PhD in Pharmaceutical Sciences. In addition, Dr. Balevic will enhance his training in the regulatory conduct of clinical trials through a unique training agreement with the FDA. His short-term goals for the K23 program are: 1) to acquire advanced knowledge and skills in PK/PD modeling; 2) develop the professional skills and techniques to lead a clinical trials team; and 3) generate a critical mass of preliminary data and publications to support an R01 grant application. The mentorship team has a history of prior collaboration, a proven record of successful mentorship of junior faculty, and has internationally recognized expertise in biomarkers of drug response, obesity, PK/PD modeling, and clinical trials. Upon successful completion of this proposal, Dr. Balevic will have acquired the necessary skillset to pursue a lifelong career in promoting safe and effective use of drugs in adults and children with rheumatic disease.